Major Depressive Disorder (MDD) is a common and important complication of Alzheimer's disease (AD) that increases the suffering of patients and their families, produces excess disability, promotes institutionalization, and hastens death. Emerging clinicopathological studies of MDD in AD suggest that the development of this behavioral complication of AD is associated with degeneration of the brainstem aminergic nuclei (SN, DR, LC) and the relative preservation of the cholinergic bnM. These neuropathologic and related neurochemical correlates of AD+MDD appear to be relatively specific for this behavioral complication of AD, and may explain aspects of the course and treatment responsiveness of MDD in this context. We propose to evaluate this primary etiologic hypothesis using 125 histopathologically-confirmed AID cases and controls who were prospectively characterized by a consortium of four NIA-funded ADRCs and the Geriatric Psychiatry Branch, DIRP, NIMI-t. All participating sites employ the Clinical Assessment of Depression in Dementia (CADD), a structured, anchored diagnostic interview that was developed to reliably diagnose and characterize Major Depressive Episodes (MDEs) in this ongoing longitudinal study. Multidimensional assessments of neurodegeneration of the brainstem nuclei are performed using rigorous stereologic analyses of immunostained frozen serial sections, and determinatons of NTs/metabolites in defined cortical and subcortical projection areas are performed using flash-frozen tissue samples by established HPLC methods. Secondary. Hypotheses explore: a) the associations of clinical subtypes on these neuropathologic and neurochemical variables, b) the mechanism of cell death in these regions, and c) the influence of a family history of MDD and APOE genotype on the emergence of MDD in AD. The long-term goal of the proposed research plan is to better define the biological substrates MDD in AD, with the intention of augmenting the knowledge base that will facilitate the development of more effective treatments, and to provide additional insight into the clinical biology of Major Mood Disorders affecting the elderly.